Present dietetic needs, predilections, and perceptions have led to the increased use of artificial sweeteners as a replacement for the "natural" sugars, including sucrose and fructose. Such artificial sweeteners are highly imperfect, including being under continual review for their long term physiological affects, yet their demand has grown unabated. Accompanying their growth as a commercial area with substantial economic impact has been a renewed emphasis on discovering and supplying new artificial sweeteners.
The ideal artificial sweetener would be noncaloric, noncariogenic, without detrimental physiological effects, and usable by diabetics. All these requirements would be met if a sweetener were not metabolized by humans and by flora which are found in the mouth and intestinal tract, and if the sweetener were either not absorbed by humans, or absorbed without effect on any internal organ. That is, the ideal sweetener should be excreted in the same form as when ingested. Another desirable feature is that it have bulk properties similar to sucrose so that it can be substituted for table sugar in many formulations. Recently, and perhaps belatedly, attention has turned toward the L-sugars as desirable artificial sweeteners. It has been known since at least 1946 that L-fructose is sweet (M. L. Wolfrom and A. Thompson, J. Am. Chem. Soc., 68, 791,793 (1946)), and since at least 1890 that L-fructose is nonfermentable (E. Fischer, Ber. Deutsch. Chem. Ges., 23, 370,389 (1890)), hence not metabolized by microorganisms generally metabolizing D-sugars. A reasonable, although not necessarily correct, inference is that it also is not metabolized by humans. Assuming that L-fructose is a sweet nonmetabolite it becomes obvious to use it as a noncaloric sweetener in many formulations. More recently Shallenberger and coworkers have demonstrated that many L-sugars have a sweetness comparable to their D-enantiomorphs. Nature, 221, 555 (1969). Cf. R. S. Shallenberger, "The Theory of Sweetness," in Sweeteners and Sweetness, pp 42-50, Edited by G. G. Birch and coworkers; R. S. Shallenberger and T. E. Acree in "The Handbook of Sensory Physiology," Vol. 4, pp 241-5, Edited by L. M. Beider (Springer Verlag, 1971).
Exploitation of the favorable properties of L-sugars is hindered by their relative unavailability. L-Fructose, for example, is not found to any significant extent in nature. This unavailability has spurred recent efforts in developing commercially feasible methods for preparing L-sugars in amounts necessary for their use as a staple of commerce. U.S. Pat. Nos. 4,371,616 and 4,421,568 describe a method of producing L-sugars, including L-idose and L-glucose, from the readily available D-glucose. Although the preparation of a number of L-sugars is described in U.S. Pat. No. 4,262,032 the focus seems to be on typical laboratory methods wholly unsuited for economical industrial production, in contrast to the process herein. U.S. Pat. No. 4,440,855 presents a flow scheme for the preparation of a mixture of L-glucose and L-mannose. The subject matter of U.S. Pat. No. 4,207,413 is L-sucrose, the enantiomer of ordinary table sugar, which can be hydrolyzed to afford L-fructose and L-glucose.
Whatever are the details of processes, actual or proposed, for the preparation of L-sugars, many employ a cyanohydrin chain-lengthening procedure which utilizes the addition of hydrogen cyanide, or more likely the addition of the elements of hydrogen cyanide (H.sup.+ and CN.sup.-) via a cyanide salt under mildly basic conditions, to a lower L-monosaccharide to gain entry to the family of L-sugars. In this application the phrase "hydrogen cyanide addition" refers to synthesis of cyanohydrins by any process which results in the addition of hydrogen cyanide to the carbonyl group of a monosaccharide. Hydrogen cyanide addition affords an epimeric pair of cyanohydrins, and often only one of the pair is desired. For example, addition of HCN to L-arabinose affords a mixture of L-mannocyanohydrin and L-glucocyanohydrin, and if, say, only the latter is desired then the presence of the former is at best useless, at worst detrimental. This invention is a means of altering the cyanohydrin product ratio resulting from the addition of hydrogen cyanide to monosaccharides. Although the invention disclosed within does not achieve total selectivity in cyanohydrin formation, which would be the optimum, it does permit adjusting the ratio of cyanohydrin products over a wide range so as to increase formation of the desired product at the expense of the other cyanohydrin.
This invention is founded on my discovery that when hydrogen cyanide addition to a monosaccharide is conducted in the presence of a reagent which complexes with the monosaccharide, the ratio of resulting cyanohydrins is changed from that obtained in the absence of the complexing agent with the ratio varying with concentration of the complexing agent. This unprecedented observation then permits adjustment of the cyanohydrin product ratio over rather wide limits, which is the goal of my invention.
The formation of complex of sugars by various agents termed complexation is reasonably well known. In this application "complex" means an entity resulting from the association of a monosaccharide with a second agent. For example, a complex may result from interaction of the unshared electron pair of one or more oxygen atoms of the monosaccharide and appropriate unoccupied orbitals of a metal cation. Such an association is an equilibrium which often can be described in terms of an association or stability constant, and is established within a time period short relative to the rate of hydrogen cyanide addition to the monosaccharide. Although it appears that the majority of complexes studied to date do involve ring formation, whether such a complex is technically a chelate is not important for the purpose of this invention.
Angyal has summarized the state of knowledge of sugar-cation complexes [S. J. Angyal, Chem. Soc. Reviews,9, 415-428 (1980)] and noted that divalent and trivalent cations with an ionic radius greater than 0.8 .ANG. complex readily with the sugar D-allose. Angyal also noted that complex formation in solution cannot be predicted from a crystal structure, citing as an example that whereas sucrose NaBr.H.sub.2 O is a crystallographic entity there is no noticeable complex formation between sucrose and sodium ions in solution (idem, ibid., 419). Angyal also showed that reactions may be affected by the presence of complexing cations, citing the synthesis of methyl furanosides as examples (idem, ibid., 425-7). However, there seems to be no predictability as to whether a given process will be affected by a complexing anion. Complexes between sugars and oxoanions, such as tungstate and molybdate, also have been described. H. J. F. Angus and coworkers, J. Chem. Soc., 1964, 3994; ibid. idem, 1965, 21.
There also has been a report that the proportions of epimeric cyanohydrins formed in the hydrogen cyanide addition to aldoses can be controlled with carbonate buffers of the alkali metals; U.S. Pat. No. 2,606,918. However, since neither carbonate nor alkali metals are known to complex to any significant extent with monosaccharides there is no reason to believe that the reported phenomenon results from, or is in any way connected to, complexation of the monosaccharide.